Single cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation
- Ottawa Hospital Research Institute, Canada
- University of Ottawa, Canada
Abstract
We sought to define the mechanism underlying lung microvascular regeneration in a model of severe acute lung injury (ALI) induced by selective lung endothelial cell ablation. Intratracheal instillation of DT in transgenic mice expressing human diphtheria toxin (DT) receptor targeted to ECs resulted in ablation of >70% of lung ECs, producing severe ALI with near complete resolution by 7 days. Using single-cell RNA sequencing, eight distinct endothelial clusters were resolved, including alveolar aerocytes (aCap) ECs expressing apelin at baseline and general capillary (gCap) ECs expressing the apelin receptor. At 3 days post injury, a novel gCap EC population emerged characterized by de novo expression of apelin, together with the stem cell marker, protein C receptor. These stem-like cells transitioned at 5 days to proliferative endothelial progenitor-like cells, expressing apelin receptor together with the pro-proliferative transcription factor, Foxm1, and were responsible for the rapid replenishment of all depleted EC populations by 7 days post injury. Treatment with an apelin receptor antagonist prevented ALI resolution and resulted in excessive mortality, consistent with a central role for apelin signaling in EC regeneration and microvascular repair. The lung has a remarkable capacity for microvasculature EC regeneration which is orchestrated by newly emergent apelin-expressing gCap endothelial stem-like cells that give rise to highly proliferative, apelin receptor positive endothelial progenitors responsible for regeneration of the lung microvasculature.
Data availability
Sequencing data have been deposited in GEO under accession codes GSE211335.
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Single Cell Transcriptomic Atlas of Lung Microvascular Regeneration after Targeted Endothelial Cell AblationNCBI Gene Expression Omnibus, GSE211335.
Article and author information
Author details
Funding
Canadian Institutes of Health Research (FDN - 143291)
- Duncan J Stewart
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Reviewing Editor
- Jalees Rehman, University of Illinois at Chicago, United States
Ethics
Animal experimentation: All animal procedures were approved by the University of Ottawa Animal Care Ethics Committee in agreement with guidelines from the Canadian Council for the Care of Laboratory Animals under protocol OHRI-2747.
Version history
- Preprint posted: July 12, 2021 (view preprint)
- Received: June 8, 2022
- Accepted: April 19, 2023
- Accepted Manuscript published: April 20, 2023 (version 1)
- Version of Record published: May 12, 2023 (version 2)
Copyright
© 2023, Godoy et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Single cell transcriptomic atlas of lung microvascular regeneration after targeted endothelial cell ablation
eLife 12:e80900.
https://doi.org/10.7554/eLife.80900
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